Functional evidence in diseased human heart fibers for multiple sensitivities of the inotropic ouabain receptor Na+,K+-ATPase (NKA).

Through contributions of many investigators from our group at the University of Cincinnati Medical Center, several facts emerged. It is clear that the rat ventricle has 2 inotropic sensitivities to ouabain (Grupp et al., 1981), related to high and low affinity ouabain binding sites (Adams et al., 1982) and the presence of an appropriate abundance of alpha and alpha + catalytic subunits of NKA (Young and Lingrel, 1987). The rat atria which demonstrate only the low affinity inotropic response (Grupp et al., 1981) also show the alpha catalytic subunit in vast predominance, with little or no alpha + (Young and Lingrel, 1987). This scheme has now also been confirmed in the ferret (Ng and Akera, 1987). By analogy, we suggest that the possibility exists that in diseased hearts part of the normally prevailing alpha catalytic subunit (sensitivity in normal human fibers about 140 nM ouabain) is converted to a more sensitive alpha + catalytic subunit leading to an increase of the ouabain sensitivity to about 50 nM. There is also an earlier occurrence of toxic effects and a reduction of the number of low affinity (alpha) ouabain binding sites, resulting in a decrease of the maximally achievable contractile force effect of ouabain. This hypothesis is presently being tested in the genetics laboratory of the University of Cincinnati Medical Center where the relative abundance of the alpha, alpha + and perhaps other isoforms of the NKA are being determined in the tissues of the same hearts from which the trabeculae used in this study were obtained.